AB0033 JANUS KINASE INHIBITOR CAN SUPPRESS STAT3 ACTIVATION IN THE SYNOVIAL TISSUES FROM THE HIP JOINT IN THE EARLY STAGE OF RAPIDLY PROGRESSIVE OSTEOARTHRITIS OF THE HIP
Authors: T. Yasuda, S. Mitsuzawa, S. Yamashita, Y. Tsukamoto, H. Takeuchi, S. Ota, E. Onishi
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Rapidly progressive osteoarthritis of the hip (RPOH) is an unusual subset of hip osteoarthritis (OA). RPOH with femoral head destruction within 12 months after the onset is associated with increased serum levels of matrix metalloproteinase-3 (MMP-3). Interleukin-6 (IL-6) signaling activates STAT3, resulting in MMP-3 production in OA synovial fibroblasts in culture. The IL-6/gp130-associated Janus kinases/STAT3 axis plays a critical role in mediating inflammatory signals. No information is currently available on STAT3 activation in the synovial tissues in the early stage of RPOH. Recently, tofacitinib and meloxicam have been shown to inhibit STAT3 activation. <h3>Objectives</h3> This study aimed to investigate suppression of phosphorylated STAT3 in the synovial tissues from the hip joint with RPOH after incubation with the potential STAT3 inhibitors. <h3>Methods</h3> Synovial tissues near the acetabular notch of the hip joint were obtained from four RPOH patients with femoral head destruction at the time of total hip replacement. Whereas the initial radiograph showed no typical feature of OA such as joint space narrowing, formation of osteophytes or bone cysts, each patient developed chondrolysis with bone destruction. Duration between the disease onset and operation were 5-7 months. The serum concentration of MMP-3 was determined within two weeks before operation. The tissue samples were incubated for 1 hour with or without tofacitinib or meloxicam. Immunohistochemical examination was performed using anti-human CD3 antibody, anti-human CD68 antibody and anti-human phospho-STAT3 antibody. The number of phospho-STAT3-positive cells was counted in the three different areas of the synovium at a magnification of X 400. A mean percentage was calculated as phospho-STAT3-positive cells in all cell counts out of the three high-power fields in each of the four patients. <h3>Results</h3> The serum concentration of MMP-3 in each RPOH patient were above the reference intervals. RPOH synovial tissues demonstrated the synovial lining hyperplasia with an increase of CD68-positive macrophages and CD3-positive T lymphocytes. STAT3 activation was found in the synovial tissues by immunohistochemistry. The majority of phospho-STAT3-positive cells were the synovial lining cells and showed negative expression of CD68 or CD3. Treatment with tofacitinib resulted in a decrease in phospho-STAT3-positive cells. Immunohistochemical intensity of phospho-STAT3 staining in the nucleus were further classified as high or low, and phospho-STAT3-positive cell numbers were counted separately as high and low intensities. Tofacitinib decreased the percentage of phospho-STAT3-positive cells with high intensity with no alteration in the percentage of low intensity. In contrast, meloxicam showed no inhibition of STAT3 activation. <h3>Conclusion</h3> This study is the first report to show that Janus kinase inhibitor tofacitinib can suppress STAT3 activation in the synovial tissues in the hip joint with RPOH, mainly in synovial fibroblasts. STAT3 may be a potential therapeutic target for prevention of joint structural damage in RPOH. Currently, no non-operative treatment modality is available for RPOH. Based on the present results, tofacitinib may be an effective intervention before the occurrence of significant joint destruction by RPOH. <h3>Acknowledgements</h3> This study was supported by Katakami Foundation for Clinical Research. <h3>Disclosure of Interests</h3> None Declared.